Schreuer M.,UZ Brussel |
Jansen Y.,UZ Brussel |
Planken S.,UZ Brussel |
Chevolet I.,UZ Gent |
And 3 more authors.
The Lancet Oncology | Year: 2017
Background Patients with BRAFV600-mutant melanoma benefit from treatment with the combination of BRAF and MEK inhibitors, but resistance and disease progression develops in most patients. Preclinical studies and case studies have indicated that acquired resistance to BRAF inhibition can be reversible. We aimed to assess the anti-tumour activity of rechallenge with BRAF plus MEK inhibition in a prospective clinical trial. Methods In this open-label, single arm, dual-centre, phase 2 academic study in Belgium, patients aged 18 years or older with BRAFV600-mutant melanoma who had previously progressed on BRAF inhibitors (with or without MEK inhibitors) and were off-treatment for at least 12 weeks, were treated with dabrafenib 150 mg orally twice per day plus trametinib 2 mg orally once per day. The primary endpoint was the proportion of patients with investigator-assessed overall response at any time (defined as complete response or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed on two occasions, at least 28 days after the first response was recorded). Analyses were done in the intention-to-treat population. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT02296996. Findings Between April 5, 2014, and Feb 2, 2016, 25 patients were enrolled and initiated treatment in our study. A partial response was documented in eight (32%) of 25 patients (95% CI 15–54; six patients had progressed on previous treatment with dabrafenib plus trametinib and two patients had progressed on previous BRAF inhibitor monotherapy). Stable disease was noted in ten patients (40%; 95% CI 21–61). Rechallenge with dabrafenib plus trametinib was well tolerated. There were no unexpected or grade 4 or 5 treatment-related adverse events. Grade 3 adverse events occurred in two patients (8%; panniculitis [n=1] and pyrexia [n=1]). Serious adverse events which occurred on study were one patient with an Addison crisis triggered by grade 2 pyrexia symptoms that resolved after discontinuation of dabrafenib and trametinib. No patients died as a result of study treatment. Interpretation Rechallenge with dabrafenib plus trametinib showed anti-tumour activity in patients who had previously progressed on BRAF inhibitors and as such, rechallenge represents a potential new treatment option for these patients. Funding Vlaamse Liga Tegen Kanker, Novartis. © 2017 Elsevier Ltd
Glorieus E.,UZ Gent |
Reenaers C.,CHU Liege |
D'Haens G.,Imelda Clinical Research Center |
Peeters H.,UZ Gent |
And 4 more authors.
Journal of Crohn's and Colitis | Year: 2013
Background and aims: Adalimumab is efficacious in inducing and maintaining remission in Crohn's disease but dose escalation is needed in 30-40% after 1. year. Attempts for dose de-escalation have not been studied. This study aimed to assess the need for, predictors, and outcome of dose escalation and de-escalation in a large cohort of adalimumab treated Crohn's patients. Methods: All consecutive patients treated with open label adalimumab for active Crohn's disease from the participating centres were included in this cohort study. A detailed retrospective chart review was performed to look for possible factors predicting outcome. Results: Eighty four percent of 720 patients had a primary response and were followed up for a median of 14. months. Thirty four percent needed escalation after a median of 7. months (0-55. months). Multivariate predictors for dose escalation were the following: prior anti-TNF use (p< 0.0001), no concomitant azathioprine or < 3. m (p< 0.02) and abnormal CRP at start (p< 0.05). Dose escalation re-induced response for at least 6. months in 67%. Only abnormal CRP at start correlated with failure of dose escalation (p= 0.02). Dose de-escalation was attempted in 54% and was successful in 63%. After a median follow-up of 14. m adalimumab was discontinued in 29% of patients. Conclusion: In this study real life nationwide cohort of Crohn's patients treated with adalimumab dose escalation was needed in 34% and was successful in 67%. Dose de-escalation was attempted in 54% and was successful in 63%. Overall 71% of patients maintained long term response on adalimumab. © 2012 European Crohn's and Colitis Organisation.
Oddens J.,Robert Bosch GmbH |
Brausi M.,B Ramazzini Hospital |
Sylvester R.,European Organization for Research and Treatment of Cancer EORTC |
Bono A.,Ospedale di Circolo |
And 8 more authors.
European Urology | Year: 2013
Background: The optimal dose and duration of intravesical bacillus Calmette-Guérin (BCG) in the treatment of non-muscle-invasive bladder cancer (NMIBC) are controversial. Objective: To determine if a one-third dose (1/3D) is not inferior to the full dose (FD), if 1 yr of maintenance is not inferior to 3 yr of maintenance, and if 1/3D and 1 yr of maintenance are associated with less toxicity. Design, setting, and participants: After transurethral resection, intermediate- and high-risk NMIBC patients were randomized to one of four BCG groups: 1/3D-1 yr, 1/3D-3 yr, FD-1 yr, and FD-3 yr. Outcome measurements and statistical analysis: The trial was designed as a noninferiority study with the null hypothesis of a 10% decrease in the disease-free rate at 5 yr. Times to events were estimated using cumulative incidence functions and compared using the Cox proportional hazards regression model. Results and limitations: In an intention-to-treat analysis of 1355 patients with a median follow-up of 7.1 yr, there were no significant differences in toxicity between 1/3D and FD. The null hypotheses of inferiority of the disease-free interval for both 1/3D and 1 yr could not be rejected. We found that 1/3D-1 yr is suboptimal compared with FD-3 yr (hazard ratio [HR]: 0.75; 95% confidence interval [CI], 0.59-0.94; p = 0.01). Intermediate-risk patients treated with FD do not benefit from an additional 2 yr of BCG. In high-risk patients, 3 yr is associated with a reduction in recurrence (HR: 1.61; 95% CI, 1.13-2.30; p = 0.009) but only when given at FD. There were no differences in progression or survival. Conclusions: There were no differences in toxicity between 1/3D and FD. Intermediate-risk patients should be treated with FD-1 yr. In high-risk patients, FD-3 yr reduces recurrences as compared with FD-1 yr but not progressions or deaths. The benefit of the two additional years of maintenance should be weighed against its added costs and inconvenience. Trial registration: This study was registered at ClinicalTrials.gov, number NCT00002990; http://clinicaltrials.gov/ct2/show/ record/NCT00002990. © 2012 European Association of Urology.
Gooren L.J.,moo 1. T.Palan |
Gooren L.J.,VU University Amsterdam |
Wierckx K.,UZ Gent |
Giltay E.J.,Leiden University
European Journal of Endocrinology | Year: 2014
Objective: The incidence of heart disease increases with age, but is lower in women than in men up to 75 years. A protective effect of female sex hormones or, alternatively, acceleration in male heart disease by testosterone at younger ages, could explain this sex difference. In contrast with the above, male-to-female transsexual subjects (MtoF) treated with estrogens (Canti-androgens) show more cardiovascular pathology than female-to-male transsexual subjects (FtoM) receiving testosterone. Why MtoF suffer more frequently from cardiovascular disease than females is as yet unclear. The mode of cross-sex hormone treatment may be a factor, and, if so, it may need adaptations. Subjects and methods: Studies in transsexual people on the effects of cross-sex hormone treatment on surrogate cardiovascular risks and on clinical endpoints were reviewed. With regard to MtoF, a parallel was sought with men with prostate cancer, undergoing androgen deprivation and estrogen administration. Results: Exposure of FtoM to testosterone was not associated with a strong increase in cardiovascular events. Aging and pre-existing cardiovascular pathology contributed to the risk of cardiovascular disease in MtoF. Use of the synthetic biopotent compound ethinyl estradiol in a dose two to four times of oral contraceptives increased cardiovascular risk substantially. The route of administration of estrogens (oral vs transdermal) may have impacted on the risks. Conclusion:MtoF shouldnot betreatedwithoralethinyl estradiol. Transdermal estrogens areprobably safer thanoral estrogens. Pre- existingcardiovascular risks shouldbe taken into considerationwhenprescribing and choosing the typeof estrogens in crosssex hormone administration (oral vs transdermal). In addition, risk factors, as they emerge with aging, should be addressed. © 2014 European Society of Endocrinology.
Aerts M.,University Hospital |
Benteyn D.,Vrije Universiteit Brussel |
Van Vlierberghe H.,UZ Gent |
Thielemans K.,Vrije Universiteit Brussel |
Reynaert H.,University Hospital
World Journal of Gastroenterology | Year: 2016
Hepatocellular carcinoma (HCC) is a frequent cancer with a high mortality. For early stage cancer there are potentially curative treatments including local ablation, resection and liver transplantation. However, for more advanced stage disease, there is no optimal treatment available. Even in the case of a "curative" treatment, recurrence or development of a new cancer in the precancerous liver is common. Thus, there is an urgent need for novel and effective (adjuvant) therapies to treat HCC and to prevent recurrence after local treatment in patients with HCC. The unique immune response in the liver favors tolerance, which remains a genuine challenge for conventional immunotherapy in patients with HCC. However, even in this "immunotolerant" organ, spontaneous immune responses against tumor antigens have been detected, although they are insufficient to achieve significant tumor death. Local ablation therapy leads to immunogenic tumor cell death by inducing the release of massive amounts of antigens, which enhances spontaneous immune response. New immune therapies such as dendritic cell vaccination and immune checkpoint inhibition are under investigation. Immunotherapy for cancer has made huge progress in the last few years and clinical trials examining the use of immunotherapy to treat hepatocellular carcinoma have shown some success. In this review, we discuss the current status of and offer some perspectives on immunotherapy for hepatocellular carcinoma, which could change disease progression in the near future. © The Author(s) 2016.
Vandenplas Y.,Vrije Universiteit Brussel |
De Hert S.G.,UZ Gent
Alimentary Pharmacology and Therapeutics | Year: 2011
Background Some probiotic strains reduce the duration of acute diarrhoea. As a result of strain and product specificity, each product needs support by clinical data. Aim In children with acute diarrhoea, to test the efficacy of the synbiotic food supplement Probiotical (Streptoccoccus thermophilus, Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium lactis, Bifidobacterium infantis, fructo-oligosaccharides). The primary end-points were duration of diarrhoea and the number of children that had a normalised stool consistency. Method A total of 111 children with acute diarrhoea (median age 40 months) were included in this randomised, prospective placebo-controlled parallel clinical trial in primary health care. All children were treated with oral rehydration solution ad libitum and with the synbiotic (n = 57) or placebo (n = 54). Results The median duration of diarrhoea was 3 days (IQ 25-75: 2-4 days) in the Probiotical group, compared with 4 days (IQ 25-75: 4-5 days) in the placebo group (P < 0.005). The number of children with normal stool consistency (defined as stool Bristol score ≤4) was higher in the synbiotic group on days 2 and 3 [21 vs. 2% (P < 0.001) and 50 vs. 24% (P < 0.001) respectively]. Less additional medication (antipyretics, antiemetics, antibiotics) was administered in the synbiotic group. Physicians were globally more satisfied with the synbiotic food supplement treatment than with placebo (P = 0.005). One patient in the placebo group was hospitalised. Conclusion The median duration of diarrhoea was significantly 1 day shorter in the synbiotic than in the placebo group, associated with decreased prescription of additional medications. © 2011 Blackwell Publishing Ltd.
Lapeere H.,UZ Gent
Nederlands Tijdschrift voor Dermatologie en Venereologie | Year: 2013
Adverse drug reaction is a general term for a wide range of reactions that can occur after the intake or administration of a drug. This is a complex problem in medicine because almost every drug can elicit a reaction. Furthermore, the clinical symptoms and signs of these reactions are very heterogeneous and the pathomechanism is often not completely clear. Every physician will encounter patients with an adverse drug reaction but there are little experts in this field. With this review we try to offer the clinician a guideline to use when faced with a suspected adverse drug reaction. © 2013 De Nederlandse Vereniging voor Dermatologie en Venereologie.
Vandenplas Y.,Vrije Universiteit Brussel |
De Hert S.,UZ Gent
Beneficial Microbes | Year: 2012
The cost/benefit ratio of probiotics in the ambulatory treatment of acute infectious gastro-enteritis with or without a synbiotic food supplement (containing fructo-oligosaccharides and probiotic strains of Streptoccoccus thermophilus, Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium lactis and Bifidobacterium infantis) has been studied. 111 children (median age 37 and 43 months for the synbiotic and placebo group, respectively) with acute infectious gastroenteritis were included in a randomised, prospective placebo-controlled trial performed in primary health care. All children were treated with an oral rehydration solution and with the synbiotic food supplement (n=57) or placebo (n=54). Physicians were allowed to prescribe additional medication according to what they considered as 'necessary'. Cost of add-on medication and total healthcare cost were calculated. Median duration of diarrhoea was 1 day shorter (95% confidence interval -0.6 to -1.9 days) in the symbiotic than in the placebo group (P<0.005). Significantly more concomitant medication (antibiotics, antipyretics, antiemetics) was prescribed in the placebo group (39 prescriptions in 28 patients) compared to the synbiotic group (12 prescriptions in 7 patients) (P<0.001). The difference was most striking for antiemetics: 28 vs. 5 prescriptions. The cost of add-on medication in the placebo group was evaluated at € 4.04/patient (median 4.97 (interquartile (IQ) 25-75: 0-4.97)) vs. € 1.13 /patient in the synbiotic arm (P<0.001). If the cost of the synbiotic is considered, median cost raised to € 7.15/patient (IQ 25-75: 7.15-7.15) (P<0.001). The extra consultations needed to prescribe the concomitant medication resulted in a higher health care cost in the placebo group (€ 14.41 vs. € 10.74/patient, P<0.001). Synbiotic food supplementation resulted in a 24 h earlier normalisation of stool consistency. Although use of the synbiotic supplementation increased cost, add-on medication and extra consultations were reduced, resulting in a reduction of health care cost of 25%. © 2012 Wageningen Academic Publishers.
De Muylder J.,Cliniques universitaires Saint Luc |
Victor J.,UZ Gent |
Cornu O.,Cliniques universitaires Saint Luc |
Kaminski L.,Cliniques universitaires Saint Luc |
Thienpont E.,Cliniques universitaires Saint Luc
Knee Surgery, Sports Traumatology, Arthroscopy | Year: 2015
Purpose: Although advocated for severe varus and valgus deformities, constrained implant designs are associated with a number of disadvantages in total knee arthroplasty (TKA). Combining a minimally invasive surgical approach with an interchangeable posterior stabilized (PS) implant design may allow adequate soft tissue balancing with a minimal amount of constraint and without residual instability. Methods: Retrospectively 51 patients operated with the minimally invasive far medial subvastus approach for severe varus or valgus deformity, who underwent primary TKA with a fully interchangeable PS implant (Vanguard, Biomet Inc., Warsaw IN, USA) between 2009 and 2013 were examined. Soft tissue releases was performed using a piecrust needling technique. Preoperative alignment and surgical parameters were collected for all patients. All patients underwent preoperative and follow-up radiographic assessment and completed a battery of clinical assessments. Results: All procedures were performed successfully, with alignment improving from a preoperative mean (SD) varus deformity of 165° (3°) and a mean (SD) valgus deformity of 196° (4.5°) to an overall mean (SD) postoperative mechanical alignment of 179.5° (3.0°). Nine patients had postoperative varus, while three patients had a postoperative valgus deviation from neutral alignment >3°. The mean change in joint line position in extension was −0.0 ± 0.6 mm. Clinical scores at final follow-up were excellent for both groups. Conclusions: Good TKA outcomes can be achieved in patients with substantial varus or valgus deformities using a combination of a minimally invasive far medial subvastus approach, interchangeable PS implants and soft tissue releases with a piecrust needling technique. Level of evidence: III. © 2014, European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).
News Article | February 3, 2017
Belgian scientists have discovered the key role of protein Taok3 in the development of type B immune cells known as MZB cells, which are responsible for making antibodies to fight diseases. Researchers are familiar with the functions of MZB cells, but the molecular processes involved in their development remained a mystery until an unrelated test revealed that Taok3 plays an essential role. Using these insights, a research team led by professor Bart Lambrecht (VIB-UGent/UZ Gent) demonstrated that mice genetically lacking in Taok3 did not develop MZB cells, and are more susceptible to bacterial infection. These insights also lead to potential new molecular therapies for genetic conditions, asthma and diabetes. The results of the study were published in leading academic journal Nature Immunology. B cells are an important part of our immune system, as they are responsible for manufacturing antibodies that fight disease. However, not all B cells are the same. The research team of professors Bart Lambrecht and Hamida Hammad (VIB-UGent) zeroed in on the development of B cells located in the spleen, labeled MZB cells. Using an unexpected finding from another project that identified a protein, Taok3, as the trigger for the development of MZB cells, prof. Lambrecht and his team showed that mice without the genetic ability to make Taok3 developed other types of B cells, but not MZB cells. As a result, they were susceptible to pneumococcus infection, a major cause of respiratory illness. A known population of B cells that makes antibodies effective against a wide range of pathogens resides in the spleen, an organ responsible for filtering bacteria and other harmful particles from the blood. Two types of B cells are formed in the spleen: MZB cells, named so because they are found in an area of the organ called the 'marginal zone', and follicular B cells. However, scientists knew little about the mechanisms governing why early B cells develop into MZB cells versus follicular B cells. Hamida Hammad (VIB-UGent): "We had a 'eureka!' moment after discovering that a little-known protein, Taok3, brings a certain proteinase, ADAM10, to the surface of the immature B cell that triggers its development into an MBZ cell. Without that special event, immature B cells can only develop into follicular B cells." In mouse strains, the team observed in vivo that without Taok3, immature B cells never 'committed' to becoming MZB cells. MZB cells generate antibodies against encapsulated bacteria such as pneumococcus when they enter the bloodstream. Hamida Hammad (VIB-UGent): "With an abundance of only follicular B cells, Taok3-free mice are less capable of fighting these types of bacteria effectively." Collaboration with other Belgian scientists revealed that proteins similar to ADAM10 were also affected in animals without Taok3, potentially contributing to the development of brain diseases characterized by too much ADAM10 activity, such as the genetic disorder fragile X syndrome, which can result in intellectual disability. Bart Lambrecht (VIB-UGent/UZ Gent): "Even more, we also found connections between Taok3 and the development of diabetes and asthma. This research has generated insights that are very relevant to new therapies to a range of important diseases. It goes to show that basic science sometimes leads to unexpected -and important - applications." Article: Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10, Hamida Hammad, Matthias Vanderkerken, Philippe Pouliot, Kim Deswarte, Wendy Toussaint, Karl Vergote, Lana Vandersarren, Sophie Janssens, Ioanna Ramou, Savvas N Savvides, Jody J Haigh, Rudi Hendriks, Manfred Kopf, Katleen Craessaerts, Bart de Strooper, John F Kearney, Daniel H Conrad & Bart N Lambrecht, Nature Immunology, doi: 10.1038/ni.3657, published online 9 January 2017.